Aerosol compressed gas packages have been used for many years for the most varied purposes. Aerosol compressed gas packages are understood to mean pressure-proof containers from which a mixture of liquefied propellant gas and active substance under pressure is released by operating a valve. Compressed gas packages are, for example, described in Sucker, Fuchs and Speiser (publishers), Pharmazeutische Technologie, Thieme, Stuttgart, 1991, p. 673-688. Aerosols and compressed gas packages are also described in List, Arzneiformenlehre, Wissenschaftliche Verlagsgesellschaft, Stuttgart, 1985, p. 8-18 and in Voigt, Lehrbuch der pharmazeutischen Technologie, VCh, Weinheim, 1987 on pages 427-436. This popular dosage form is also extensively described by Thoma, Aerosole, published by the author, Frankfurt am Main, 1979. In the medical sector they are advantageously used when active substances have to be directly transported to the lungs and deposited there. The advantage of aerosol compressed gas packages lies in the fact that their use produces a cloud of finely dispersed particles which can be inspired by the patient. The result is a rapid onset of action at the site of action--the lung--which is, for example, of critical importance in bronchial asthma therapy. On the other hand, local application of this nature directly into the lung can keep the dosage low in the prevention of asthma attacks using prophylactically acting substances. This minimizes the appearance of undesirable side effects compared to application via the gastro-intestinal tract.
Aerosol compressed gas packages have therefore found wide use in the treatment of respiratory tract disorders. They are simply, safe and economically priced. Possible problems in coordinating the inspiration of the patient and triggering of an aerosol burst can be avoided either by expansion chambers (spacers) interposed between the aerosol packaging and the mouth of the patient, or by special constructions of the inhalers in which the inspiration of the patient triggers the aerosol burst.
Apart from use in bronchial asthma prophylaxis and in the treatment of acute asthma attacks, the formulation of the invention can also find use as a nasal spray and for application as a mouth spray (lingual and buccal application).
CFCs (fluorinated chlorinated hydrocarbons) have hitherto been used as propellants for dosage aerosols. The following fluorinated chlorinated hydrocarbons and hydrocarbons can, for example, be used as propellants: pentane, n-butane, iso-butane, TG 11, TG 12, TG 21, TG 22, TG 23, TG 113, TG 114, TG 115, TG 142b and TG C 318.
The type designation of the fluorinated chlorinated hydrocarbons is derived from the following code system: Number in unit place=number of fluorine atoms (F) Number in tens place minus 1=number of hydrogen atoms (H) Number in hundreds place plus 1=number of carbon atoms (C) Number of free valencies=number of chlorine atoms (C1)
Since the postulation of the "ozone theory" (breakdown of the ozone in the stratosphere because of CFCs and other organic compounds containing chlorine) there has been a search for liquid gases which can serve as propellants and which are neither combustible, nor liable to break down ozone and which are, moreover, not harmful to health.
For some time, non-chlorinated fluorohydrocarbons such as 1,1,1,2-tetrafluoroethane (TG 134a) or 2H-heptafluoropropane (TG 227) have been used.
Apart from TG 134a and TG 227, mention may also be made of TG 152a (difluoroethane, CH.sub.3 CHF.sub.2), TG 143a (trifluoroethane, CH.sub.3 CF.sub.3) and TG 161 (fluoroethane, CH.sub.3 CH.sub.2 F).
However, it is a disadvantage of these propellants that the suspension stabilizers and valve lubricants, needed for their use, are not sufficiently soluble in them. Thus the use of TG 134a requires about 25% ethanol in order to dissolve the sorbitan trioleate (Span.RTM.85) hitherto used in aerosol suspensions to an adequate extent (see Published European Patent Application EP 372 777 A 2). It is, for example, also possible to use the following compounds: multivalent alcohols such as glycerol, esters such as ethyl acetate, ketones such as acetone and hydrocarbons such as hexane and heptane, pentane and also isopropanol. A disadvantage of such high concentrations is that the active substance present in the suspension may tend to dissolve, resulting in a risk of particle growth. If the active substance particles grow during storage of a suspension of this type above a size of 10 .mu.m there may be blockage of the aerosol valve. In addition, there may be a reduction in effectiveness of the aerosol, since the active substance particles can no longer reach the deeper parts of the lungs because of their size.
There is consequently an urgent need for substances which
are physiologically acceptable PA1 are technologically suitable to stabilize aerosol suspensions of TG 134a or TG 227 and to improve the function of the dosage valve PA1 are soluble in TG 134a or TG 227 without, or using the smallest amounts of, other physiologically acceptable solubilizers PA1 have an acceptable taste. PA1 physiologically acceptable (comparable to sorbitan trioleate (=Span.RTM.85)) PA1 technologically suited to stabilize aerosol suspensions of TG 134a and/or TG 227 and to improve the function of the dosage valve PA1 soluble in TG 134a or TG 227 in the presence of less than 1-2% ethanol or comparable alcohols PA1 acceptable in taste PA1 Tagat.RTM.O PA1 Tagat.RTM.O2